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WO2023159086A1 - Composés de quinazoline et leur utilisation en tant qu'inhibiteurs de protéines kras mutantes - Google Patents

Composés de quinazoline et leur utilisation en tant qu'inhibiteurs de protéines kras mutantes Download PDF

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WO2023159086A1
WO2023159086A1 PCT/US2023/062687 US2023062687W WO2023159086A1 WO 2023159086 A1 WO2023159086 A1 WO 2023159086A1 US 2023062687 W US2023062687 W US 2023062687W WO 2023159086 A1 WO2023159086 A1 WO 2023159086A1
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Prior art keywords
cancer
fluoro
amino
compound
methoxy
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English (en)
Inventor
Xiaofen Li
Wei Zhao
Ryan Wurz
Michael YAMANO
Imelda HOT
Rene Rahimoff
Liping Pettus
Jose Medina
Brian Lanman
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Amgen Inc
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Amgen Inc
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Priority to CA3251001A priority Critical patent/CA3251001A1/fr
Priority to JP2024547690A priority patent/JP2025508702A/ja
Priority to AU2023222076A priority patent/AU2023222076A1/en
Priority to EP23711641.3A priority patent/EP4479401A1/fr
Priority to CN202380032897.3A priority patent/CN118974055A/zh
Priority to US18/838,954 priority patent/US20250163064A1/en
Priority to MX2024010045A priority patent/MX2024010045A/es
Publication of WO2023159086A1 publication Critical patent/WO2023159086A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present disclosure provides compounds having activity as inhibitors of mutant KRAS proteins.
  • This disclosure also provides pharmaceutical compositions comprising the compounds, uses and methods of treating certain disorders, such as cancer, including but not limited to non-smail cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma.
  • cancer including but not limited to non-smail cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma.
  • KRAS the Kirsten rat sarcoma viral oncogene homologue
  • tire KRAS protein has historically proven resistant to direct inhibition.
  • KRAS is a G-protein that couples extracellular mitogenic signaling to intracellular, pro- proliferative responses.
  • KRAS serves as an intracellular “on/off” sw itch.
  • Mitogen stimulation induces the binding of GTP to KRAS, bringing about a conformational change which enables the interaction of KRAS with downstream effector proteins, leading to cellular proliferation.
  • pro-proliferative signaling is regulated by the action of GTPase-activating proteins (GAPs), which return KRAS to its GDP-bound, non-proliferative state. Mutations in KRAS impair the regulated cycling of KRAS between these GDP- and GTP -bound states, leading to the accumulation of the GTP -bound active state and dysregulated cellular proliferation (Simanshu et al., 2017).
  • KRAS G12C inhibitors While some progress has been made on KRAS G12C inhibitors, there is a continued interest and effort to develop inhibitors of KRAS, particularly inhibitors of other KRAS such as KRAS G12D, G12V, G12A or G12S. Thus, there is a need to develop new inhibitors for KRAS G12D, G12V, G12A, G12S or G12C for the treatment of disorders, such as cancer.
  • the present application is directed to a compound of formula (I): or tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, wherein; --- is a single bond or a double bond; W is C, CH or N, wherein when W is N, is a single bond; X is a bond, CH 2 , O, S, S(O), S(O)(NR z ) or S(O) 2 ; n is 0, 1, 2, or 3; m is 0, 1, 2, 3 or 4; each R x is hydroxyl, halogen, oxo, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, -T-R y or two R x taken together with the same carbon or adjacent carbon atoms can form C 3-7 cycloalkyl or a 5-7 membered heterocycloalkyl, wherein each C 3-7 cycloalkyl or 5-7 membered heterocycloalkyl, where
  • a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt of said compound and a pharmaceutically acceptable excipient.
  • a compound of Formula I, or a pharmaceutically acceptable salt of said compound, or the pharmaceutical composition as described herein for use in treating cancer is provided herein.
  • each R x is hydroxyl, halogen, oxo, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, -T-R y or two R x taken together with the same carbon or adjacent carbon atoms can form C 3-7 cycloalkyl or a 5-7 membered heterocycloalkyl, wherein each C 3-7 cycloalkyl or 5-7 membered heterocycloalkyl is further substituted with 0-3 occurrences of R y or two R
  • embodiment 2 is the compound according to embodiment 1, wherein Z is N.
  • embodiment 3 is the compound according to any one of embodiments 1-2, wherein L is -C 1-4 alkylene or -O-C 1-4 alkylene.
  • embodiment 4 is the compound according to embodiment 3, wherein L is -C 1-4 alkylene (e.g., -methylene).
  • embodiment 5 is the compound according to embodiment 3, wherein L is -O-C 1-4 alkylene (e.g., -O- methylene or -O-2,2-dimethylethylene).
  • embodiment 6 is the compound according to embodiment 5, wherein L is -O-methylene.
  • embodiment 7 is the compound according to embodiment 6, wherein R 1 is 7- (hexahydro-1H-pyrrolizine) substituted with 0-3 occurrences of R 5 .
  • embodiment 8 is the compound according to embodiment 7, wherein R 1 is 7-(hexahydro-1H-pyrrolizine) substituted with one occurrence of R 5 .
  • embodiment 9 is the compound according to embodiment 8, wherein R 5 is halogen (e.g., fluorine).
  • embodiment 10 is the compound according to embodiment 7, wherein R 1 is 7-(hexahydro-1H-pyrrolizine) substituted with 2 occurrences of R 5 .
  • embodiment 11 is the compound according to embodiment 10, wherein both R 5 are halogen (e.g., fluorine).
  • embodiment 12 is the compound according to embodiment 6, wherein R 1 is 2- pyrrolidine substituted with 0-3 occurrences of R 5 .
  • embodiment 13 is the compound according to embodiment 12, wherein R 1 is 2-pyrrolidine substituted with 2 occurrences of R 5 .
  • embodiment 14 is the compound according to embodiment 13, wherein one R 5 is C 1-4 alkyl (e.g., methyl) and the other R 5 is halogen (e.g., fluorine).
  • embodiment 15 is the compound according to embodiment 5, wherein L is -O- isopentanylene (i.e., -O-2,2-dimethylethylene).
  • embodiment 16 is the compound according to embodiment 15, wherein R 1 is hydroxyl.
  • embodiment 17 is the compound according to embodiment 4, wherein L is - methylene.
  • embodiment 18 is the compound according to embodiment 17, wherein R 1 is N-morpholinyl substituted with 0-3 occurrences of R 5 .
  • embodiment 19 is the compound according to embodiment 18, wherein R 1 is N-morpholinyl substituted with 0 occurrences of R 5 .
  • embodiment 20 is the compound according to embodiments 1-19, wherein L- R 1 is Provided herein as embodiment 21 is the compound according to embodiment 20, wherein L-R 1 is Provided herein as embodiment 22 is the compound according to embodiment 20, wherein L-R 1 is Provided herein as embodiment 23 is the compound according to embodiment 20, wherein L-R 1 is Provided herein as embodiment 24 is the compound according to embodiment 20, wherein L-R 1 is Provided herein as embodiment 25 is the compound according to embodiment 20, wherein L-R 1 is Provided herein as embodiment 26 is the compound according to any one of embodiments 1-25, wherein W is N.
  • Provided herein as embodiment 27 is the compound according to embodiment 26, wherein X is O.
  • embodiment 28 is the compound according to embodiment 27, wherein n is 1 and m is 2 or m is 1 and n is 2.
  • embodiment 29 is the compound according to embodiment 28, wherein p is 0.
  • embodiment 30 is the compound according to embodiment 28, wherein p is 1.
  • embodiment 31 is the compound according to embodiment 30, wherein R x is hydroxyl, oxo, halogen or -T-R y .
  • embodiment 32 is the compound according to embodiment 31, wherein R x is hydroxyl, oxo, fluorine or -SO 2 NH 2 .
  • embodiment 33 is the compound according to embodiment 32, wherein R x is hydroxyl, oxo or fluorine.
  • embodiment 34 is the compound according to embodiment 28, wherein p is 2.
  • embodiment 35 is the compound according to embodiment 34, wherein each R x is hydroxyl, halogen, C 1-4 alkyl, C 1-4 haloalkyl or two R x are taken together with the carbon atoms to which they are attached to form a bridged ring with the bridge atoms are -C 1-4 alkylene.
  • embodiment 36 is the compound according to embodiment 35, wherein one R x is hydroxyl and the other R x is C 1-4 alkyl (e.g., methyl or ethyl).
  • embodiment 37 is the compound according to embodiment 35, wherein both R x are halogen (e.g., fluorine).
  • embodiment 38 is the compound according to embodiment 35, wherein one R x is hydroxyl and the other R x is C 1-4 haloalkyl (e.g., difluoromethyl).
  • embodiment 39 is the compound according to embodiment 35, wherein two R x are taken together with the carbon atoms to which they are attached to form a bridged ring wherein the bridge atoms are methylene or ethylene.
  • embodiment 40 is the compound according to embodiment 27, wherein n is 2 and m is 2.
  • embodiment 41 is the compound according to embodiment 40, wherein p is 0.
  • embodiment 42 is the compound according to embodiment 27, wherein m is 1 and n is 3.
  • embodiment 43 is the compound according to embodiment 42, wherein p is 0.
  • embodiment 44 is the compound according to embodiment 26, wherein X is S(O) 2 .
  • embodiment 45 is the compound according to embodiment 44, wherein n is 1 and m is 2 or m is 1 and n is 2.
  • embodiment 46 is the compound according to embodiment 45, wherein p is 0.
  • embodiment 47 is the compound according to any one of embodiments 26-46, wherein
  • Provided herein as embodiment 48 is the compound according to embodiment 47, wherein Provided herein as embodiment 49 is the compound according to embodiment 47, wherein Provided herein as embodiment 50 is the compound according to embodiment 47, wherein Provided herein as embodiment 51 is the compound according to embodiment 47, wherein Provided herein as embodiment 52 is the compound according to embod iment 47, wherein Provided herein as embodiment 53 is the compound according to embodiment 47, wherein Provided herein as embodiment 54 is the compound according to embodiment 47, wherein Provided herein as embodiment 55 is the compound according to embodiment 47, wherein Provided herein as embodiment 56 is the compound according to embodiment 47, wherein Provided herein as embodiment 57 is the compound according to embodiment 47, wherein Provided herein as embodiment 58 is the compound according to embodiment 47, wherein Provided herein as embodiment 59 is the compound according to embodiment 47, wherein Provided herein as embodiment 60 is the compound according to embodiment 47, wherein Provided herein as embodiment 61 is the compound according to embodiment 47, wherein Provided herein as embodiment 62 is
  • embodiment 67 is the compound according to embodiment 66, wherein n is 0 and m is 1 or m is 0 and n is 1.
  • embodiment 68 is the compound according to embodiment 67, wherein p is 1.
  • embodiment 69 is the compound according to embodiment 68, wherein R x is C 1-4 alkyl, cyano or -T-R y .
  • embodiment 70 is the compound according to embodiment 69, wherein R x is methyl, cyano, -CH 2 OH, -CH 2 CN or -CH 2 OMe.
  • embodiment 71 is the compound according to embodiment 67, wherein p is 2.
  • embodiment 72 is the compound according to embodiment 71, wherein each R x is C 1-4 alkyl, hydroxyl or -T-R y or two R x are taken together with the same carbon atom to form a 4-7 membered heterocycloalkyl substituted with 0-3 occurrences of R y .
  • embodiment 73 is the compound according to embodiment 72, wherein one R x is methyl and the other R x is -CH 2 OH.
  • embodiment 74 is the compound according to embodiment 72, wherein one R x is methyl and the other R x is hydroxyl.
  • embodiment 75 is the compound according to embodiment 72, wherein both R x are taken together with the same carbon atom to form a 2- tetrahydrothiophene substituted with 2 occurrences of R y .
  • embodiment 76 is the compound according to embodiment 75, wherein both R y are oxo.
  • embodiment 77 is the compound according to any one of embodiments 66-76, wherein Provided herein as embodiment 78 is the compound according to embodiment 77, wherein Provided herein as embodiment 79 is the compound according to embodiment 77, wherein Provided herein as embodiment 80 is the compound according to embodiment 77, wherein Provided herein as embodiment 81 is the compound according to embodiment 77, wherein Provided herein as embodiment 82 is the compound according to embodiment 77, wherein Provided herein as embodiment 83 is the compound according to embodiment 77, wherein Provided herein as embodiment 84 is the compound according to embodiment 77, wherein Provided herein as embodiment 85 is the compound according to embodiment 77, wherein Provided herein as embodiment 86 is the compound according to embodiment 77, wherein Provided herein as embodiment 87 is the compound according to embodiment 66, wherein n is 1 and m is 1.
  • embodiment 88 is the compound according to embodiment 87, wherein p is 0.
  • embodiment 89 is the compound according to embodiment 87, wherein p is 1.
  • embodiment 90 is the compound according to embodiment 89, wherein R x is hydroxyl, cyano or -T-R y .
  • embodiment 91 is the compound according to embodiment 90, wherein R x is hydroxyl, cyano or -S(O) 2 -NH 2 .
  • embodiment 92 is the compound according to embodiment 87, wherein p is 2.
  • embodiment 93 is the compound according to embodiment 92, wherein each R x is hydroxyl, C 1-4 alkyl, -T-R y or two R x are taken together with the same carbon atom to form a C 3-7 cycloalkyl or 4-7 membered heterocycloalkyl substituted with 0-3 occurrences of R y .
  • embodiment 94 is the compound according to embodiment 93, wherein one R x is hydroxyl and the other R x is methyl.
  • embodiment 95 is the compound according to embodiment 93, wherein one R x is hydroxyl and the other R x is ethyl.
  • embodiment 96 is the compound according to embodiment 93, wherein one R x is methyl and the other R x is -CH 2 OH.
  • embodiment 97 is the compound according to embodiment 93, wherein one R x is methyl and the other R x is -C(O)NH 2 .
  • embodiment 98 is the compound according to embodiment 93, wherein two R x are taken together with the same carbon atom to form a cyclobutyl substituted with one occurrence of R y .
  • embodiment 99 is the compound according to embodiment 98, wherein R y is oxo or hydroxyl.
  • embodiment 100 is the compound according to embodiment 93, wherein two R x are taken together with the same carbon atom to form a 2-azetidinyl substituted with one occurrence of R y .
  • embodiment 101 is the compound according to embodiment 100, wherein R y is oxo.
  • embodiment 102 is the compound according to embodiment 93, wherein two R x are taken together with the same carbon atom to form a 3-azetidinyl substituted with one occurrence of -T-R y .
  • embodiment 103 is the compound according to embodiment 102, wherein -T- R y is -SO 2 -Me.
  • embodiment 104 is the compound according to embodiment 93, wherein two R x are taken together with the same carbon atom to form a 5-oxazolidinyl substituted with one occurrence of R y .
  • embodiment 105 is the compound according to embodiment 104, wherein R y is oxo.
  • embodiment 106 is the compound according to embodiment 93, wherein two R x are taken together with the same carbon atom to form a 3-oxetanyl substituted with 0 occurrences of R y .
  • embodiment 107 is the compound according to embodiment 93, wherein two R x are taken together with the same carbon atom to form a 2-oxetanyl substituted with 0 occurrences of R y .
  • embodiment 108 is the compound according to embodiment 93, wherein two R x are taken together with the same carbon atom to form a 3-tetrahydrothiophenyl substituted with two occurrences of R y .
  • embodiment 109 is the compound according to embodiment 108, wherein both R y are oxo.
  • embodiment 110 is the compound according to embodiment 93, wherein two R x are taken together with the same carbon atom to form a 2-thietanyl substituted with two occurrences of R y .
  • embodiment 111 is the compound according to embodiment 110, wherein both R y are oxo.
  • embodiment 112 is the compound according to embodiment 93, wherein two R x are taken together with the same carbon atom to form a 2-tetrahydrofuranyl substituted with 0 occurrences of R y .
  • embodiment 113 is the compound according to embodiment 93, wherein two R x are taken together with the same carbon atom to form a 3-tetrahydrofuranyl substituted with 0 occurrences of R y .
  • Provided herein as embodiment 114 is the compound according to any one of embodiments 87- 113, wherein Provided herein as embodiment 115 is the compound according to embodiment 114, wherein Provided herein as embodiment 116 is the compound according to embodiment 114, wherein Provided herein as embodiment 117 is the compound according to embodiment 114, wherein Provided herein as embodiment 118 is the compound according to embodiment 114, wherein Provided herein as embodiment 119 is the compound according to embodiment 114, wherein Provided herein as embodiment 120 is the compound according to embodiment 114, wherein Provided herein as embodiment 121 is the compound according to embodiment 114, wherein Provided herein as embodiment 122 is the compound according to embodiment 114, wherein Provided herein as embodiment 123 is the compound according to embodiment 114, wherein wherein
  • embodiment 138 is the compound according to embodiment 137, wherein p is 0.
  • embodiment 139 is the compound according to embodiment 137, wherein p is 1.
  • embodiment 140 is the compound according to embodiment 139, wherein R x is halogen, cyano, oxo, hydroxyl, C 1-4 alkyl or -T-R y .
  • embodiment 141 is the compound according to embodiment 140, wherein R x is fluorine, cyano, oxo, hydroxyl or -SO 2 -NH 2 .
  • embodiment 142 is the compound according to embodiment 137, wherein p is 2.
  • embodiment 143 is the compound according to embodiment 142, wherein one R x is hydroxyl and the other R x is C 1-4 alkyl (e.g., methyl).
  • embodiment 144 is the compound according to embodiment 137, wherein p is 3.
  • embodiment 145 is the compound according to embodiment 144, wherein two R x are taken together with the carbon atoms to which they are attached to form a bridged ring wherein the bridge atoms are -C 1-4 alkylene and the remaining R x is hydroxyl.
  • embodiment 146 is the compound according to embodiment 145, wherein two R x are taken together with the carbon atoms to which they are attached to form a methylene bridged ring and the remaining R x is hydroxyl.
  • embodiment 147 is the compound according to embodiment 66, wherein n is 2 and m is 2.
  • embodiment 148 is the compound according to embodiment 147, wherein p is 0.
  • embodiment 149 is the compound according to any one of embodiments 137- 148, wherein Provided herein as embodiment 150 is the compound according to embodiment 149, wherein Provided herein as embodiment 151 is the compound according to embodiment 149, wherein Provided herein as embodiment 152 is the compound according to embodiment 149, wherein Provided herein as embodiment 153 is the compound according to embodiment 149, wherein Provided herein as embodiment 154 is the compound according to embodiment 149, wherein Provided herein as embodiment 155 is the compound according to embodiment 149, wherein Provided herein as embodiment 156 is the compound according to embodiment 149, wherein Provided herein as embodiment 157 is the compound according to embodiment 149, wherein Provided herein as embodiment 158 is the compound according to embodiment 149, wherein Provided herein as embodiment 159 is the compound according to embodiment 149, wherein .
  • embodiment 165 is the compound according to embodiment 164, wherein n is 1 and m is 1.
  • embodiment 166 is the compound according to embodiment 165, wherein p is 1.
  • embodiment 167 is the compound according to embodiment 166, wherein R x is hydroxyl.
  • embodiment 170 is the compound according to embodiment 169, wherein X is O.
  • embodiment 171 is the compound according to embodiment 170, wherein --- is a double bond.
  • embodiment 172 is the compound according to embodiment 171, wherein n is 0 and m is 2.
  • embodiment 173 is the compound according to embodiment 172, wherein p is 0.
  • embodiment 174 is the compound according to any one of embodiments 169- 173, wherein Provided herein as embodiment 175 is the compound according to any one of embodiments 1-2, wherein W is -CH-.
  • embodiment 176 is the compound according to embodiment 175, wherein X is a bond.
  • embodiment 177 is the compound according to embodiment 176, wherein is a single bond.
  • embodiment 178 is the compound according to embodiment 177, wherein n is 0 and m is 0.
  • embodiment 179 is the compound according to embodiment 178, wherein p is 0.
  • embodiment 180 is the compound according to any one of embodiments 175- 180, wherein Provi ded herein as embodiment 181 is the compound according to any one of embodiments 1- 180, wherein R 8 is amino and R 9 is cyano.
  • embodiment 182 is the compound according to any one of embodiments 1- 181, wherein R 2 is halogen, C 1-4 alkyl, C 2-4 alkenyl or cyano.
  • embodiment 183 is the compound according to embodiment 182, wherein R 2 is chlorine, methyl, ethyl, vinyl or cyano.
  • embodiment 184 is the compound according to embodiment 182, wherein R 2 is chlorine.
  • embodiment 185 is the compound according to embodiment 182, wherein R 2 is methyl or ethyl.
  • embodiment 186 is the compound according to embodiment 182, wherein R 2 is methyl.
  • embodiment 187 is the compound according to embodiment 182, wherein R 2 is ethyl.
  • embodiment 188 is the compound according to embodiment 182, wherein R 2 is vinyl (i.e., 2-ethenyl).
  • embodiment 189 is the compound according to embodiment 182, wherein R 2 is cyano.
  • embodiment 190 is the compound according to any one of embodiments 1- 189, wherein R 4 is halogen (e.g., fluorine).
  • embodiment 191 is the compound according to any one of embodiments 1- 190, wherein R 4 is fluorine.
  • embodiment 192 is the compound according to any one of embodiments 1- 191, wherein R 3 is hydrogen or halogen (e.g., fluorine).
  • embodiment 193 is the compound according to embodiment 192, wherein R 3 is hydrogen.
  • embodiment 194 is the compound according to embodiment 192, wherein R 3 is fluorine.
  • embodiment 195 is the compound according to any one of 1-194, wherein R q is hydrogen.
  • embodiment 196 is the compound according to any one of embodiments 1-194, wherein R q is halogen (e.g., chlorine or fluorine).
  • embodiment 197 is the compound according to any one of embodiments 1-194, wherein R q is C 1-4 alkyl (e.g., methyl).
  • embodiment 198 is the compound according to any one of embodiments 1- 197, wherein R q is attached as illustrated in Formula (IIa):
  • embodiment 199 is the compound according to any one of embodiments 1- 198, wherein R q is attached as illustrated in Formula (IIb):
  • embodiment 200 is the compound according to any one of embodiments 1- 199, wherein R q is attached as illustrated in Formula (IIc):
  • embodiment 201 is the compound according to any one of embodiments 1- 200, wherein R q is attached as illustrated in Formula (IId):
  • embo diment 201 is the compound according to embodiment 1, wherein the compound is selected from one of the following compounds: 2-Amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)
  • embodiment 202 is the compound according to embodiment 1, wherein the compound is selected from one of the following compounds: 2-Amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1,5- oxazocan-5-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-Amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(6- hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile; 2-Amino-4-(6-chloro-8-fluoro
  • embodiment 203 is the compound according to embodiment 1, wherein the compound is selected from one of the following compounds: 2-Amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1,5- oxazocan-5-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (Isomer 1); 2-Amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(6- hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (Isomer 1); 2-Amino-4-(
  • embodiment 204 is the compound according to embodiment 1, wherein the compound is selected from one of the following compounds: 2-Amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(1,5- oxazocan-5-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (Isomer 1); 2-Amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-4-(6- hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (Isomer 1); 2-Amino-4-(
  • a pharmaceutical composition comprising a compound disclosed herein in combination with one or more pharmaceutically acceptable excipients, such as diluents, carriers, adjuvants and the like, and, if desired, other active ingredients. See, e.g., Remington: The Science and Practice of Pharmacy, Volume I and Volume II, twenty-second edition, edited by Loyd V.
  • a pharmaceutical composition comprises a therapeutically effective amount of a compound disclosed herein.
  • the compound(s) disclosed herein may be administered by any suitable route in the form of a pharmaceutical composition adapted to such a route and in a dose effective for the treatment intended.
  • compositions presented herein may, for example, be administered orally, mucosally, topically, transdermally, rectally, pulmonarily, parentally, intranasally, intravascularly, intravenously, intraarterial, intraperitoneally, intrathecally, subcutaneously, sublingually, intramuscularly, intrasternally, vaginally or by infusion techniques, in dosage unit formulations containing conventional pharmaceutically acceptable excipients.
  • the pharmaceutical composition may be in the form of, for example, a tablet, chewable tablet, minitablet, caplet, pill, bead, hard capsule, soft capsule, gelatin capsule, granule, powder, lozenge, patch, cream, gel, sachet, microneedle array, syrup, flavored syrup, juice, drop, injectable solution, emulsion, microemulsion, ointment, aerosol, aqueous suspension, or oily suspension.
  • the pharmaceutical composition is typically made in the form of a dosage unit containing a particular amount of the active ingredient.
  • embodiment 205 is a pharmaceutical composition comprising the compound according to any one of embodiments 1-204, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, and a pharmaceutically acceptable excipient.
  • embodiment 206 is a compound according to any one of embodiments 1-204, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer, or the pharmaceutical composition according to embodiment 205 for use as a medicament.
  • the compounds described herein are to be understood to include all stereoisomers, tautomers, or pharmaceutically acceptable salts of any of the foregoing or solvates of any of the foregoing. Accordingly, the scope of the methods and uses provided in the instant disclosure is to be understood to encompass also methods and uses employing all such forms.
  • the compounds provided herein may be useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. For example, animals including horses, dogs, and cats may be treated with compounds provided herein.
  • the disclosure provides methods of using the compounds or pharmaceutical compositions of the present disclosure to treat disease conditions, including but not limited to conditions implicated by KRAS G12D, G12V, G12A, G12S or G12C mutation (e.g., cancer).
  • the cancer types are non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma.
  • KRAS G12D mutations occur with the alteration frequencies shown in the table below (TCGA data sets; 1-3 For example, the table shows that 32.4% of subjects with pancreatic cancer have a cancer wherein one or more cells express KRAS G12D mutant protein. Accordingly, the compounds provided herein, which bind to KRAS G12D (see Section entitled “Biological Evaluation” below) are useful for treatment of subjects having a cancer, including, but not limited to the cancers listed in the table below.
  • Provided herein as embodiment 207 is a compound according to any one of embodiments 1-204 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to embodiment 205 for use in treating cancer.
  • Embodiment 208 is a compound according to any one of Embodiments 1-204 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to Embodiment 205 for use in treating cancer, wherein one or more cells express KRAS G12D, G12V, G12A, G12S or G12C mutant protein.
  • Embodiment 209 is the compound or pharmaceutical composition for use of Embodiment 207 or 208, wherein the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, small bowel cancer, appendiceal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
  • the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, small bowel cancer, appendiceal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer,
  • Embodiment 210 is a use of the compound according to any one of Embodiments 1-204 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to Embodiment 205 in the preparation of a medicament for treating cancer.
  • Embodiment 211 is a use of the compound according to any one of Embodiments 1-204 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to Embodiment 205 in the preparation of a medicament for treating cancer, wherein one or more cells express KRAS G12D, G12V, G12A, G12S or G12C mutant protein.
  • Embodiment 212 is the use according to Embodiment 210 or 211, wherein the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
  • the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendoc
  • Embodiment 213 is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according to any one of to any one of Embodiments 1-204 or a pharmaceutically acceptable salt thereof.
  • Embodiment 214 is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according to any one of to any one of Embodiments 1-204 or a pharmaceutically acceptable salt thereof, wherein one or more cells express KRAS G12D, G12V, G12A, G12S or G12C mutant protein.
  • Embodiment 215 is the method according to Embodiment 213 or 214, wherein the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendocrine cancer, bladder cancer, myelodysplastic/myeloproliferative neoplasms, head and neck cancer, esophagogastric cancer, soft tissue sarcoma, mesothelioma, thyroid cancer, leukemia, or melanoma.
  • the cancer is non-small cell lung cancer, small bowel cancer, appendiceal cancer, colorectal cancer, cancer of unknown primary, endometrial cancer, mixed cancer types, pancreatic cancer, hepatobiliary cancer, small cell lung cancer, cervical cancer, germ cell cancer, ovarian cancer, gastrointestinal neuroendoc
  • Embodiment 216 is the method according to Embodiment 213 or 214, wherein the cancer is non-small cell lung cancer, colorectal cancer, pancreatic cancer, appendiceal cancer, endometrial cancer, esophageal cancer, cancer of unknown primary, ampullary cancer, gastric cancer, small bowel cancer, sinonasal cancer, bile duct cancer, or melanoma.
  • Embodiment 217 is the method according to Embodiment 216, wherein the cancer is non-small cell lung cancer.
  • Embodiment 218 is the method according to Embodiment 216, wherein the cancer is colorectal cancer.
  • Embodiment 219 is the method according to Embodiment 216, wherein the cancer is pancreatic cancer.
  • Embodiment 220 is the method according to anyone of Embodiments 213- 219, wherein the subject has a cancer that was determined to have one or more cells expressing the KRAS G12D, G12V, G12A, G12S or G12C mutant protein prior to administration of the compound or a pharmaceutically acceptable salt thereof.
  • Combination Therapy The present disclosure also provides methods for combination therapies in which an agent known to modulate other pathways, or other components of the same pathway, or even overlapping sets of target enzymes are used in combination with a compound of the present disclosure or a pharmaceutically acceptable salt thereof.
  • such therapy includes but is not limited to the combination of one or more compounds of the disclosure with chemotherapeutic agents, therapeutic antibodies, and radiation treatment, to provide a synergistic or additive therapeutic effect.
  • chemotherapeutic agents include but is not limited to the combination of one or more compounds of the disclosure with chemotherapeutic agents, therapeutic antibodies, and radiation treatment, to provide a synergistic or additive therapeutic effect.
  • chemotherapeutic agents include but is not limited to the combination of one or more compounds of the disclosure with chemotherapeutic agents, therapeutic antibodies, and radiation treatment, to provide a synergistic or additive therapeutic effect.
  • Embodiment 198 is the method according to anyone of Embodiments 190- 197, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an Aurora kinase A inhibitor, AKT inhibitor, arginase inhibitor, CDK4/6 inhibitor, ErbB family inhibitor, ERK inhibitor, FAK inhibitor, FGFR inhibitor, glutaminase inhibitor, IGF-1R inhibitor, KIF18A inhibitor, MCL-1 inhibitor, MEK inhibitor, mTOR inhibitor, PD-1 inhibitor, PD-L1 inhibitor, PI3K inhibitor, Raf kinase inhibitor, SHP2 inhibitor, SOS1 inhibitor, Src kinase inhibitor, or one or more chemotherapeutic agent.
  • the second compound is an Aurora kinase A inhibitor, AKT inhibitor, arginase inhibitor, CDK4/6 inhibitor, ErbB family inhibitor, ERK inhibitor, FAK inhibitor, FGFR inhibitor, glutaminase inhibitor, IGF-1R inhibitor, K
  • the second compound is administered as a pharmaceutically acceptable salt. In another embodiment the second compound is administered as a pharmaceutical composition comprising the second compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • Aurora Kinase A Inhibitors Provided herein is the method according to anyone of Embodiments 213-220, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an Aurora kinase A inhibitor.
  • Aurora kinase A inhibitors for use in the methods provided herein include, but are not limited to, alisertib, cenisertib, danusertib, tozasertib, LY3295668 ((2R,4R)-1-[(3-chloro-2- fluorophenyl)methyl]-4-[[3-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyridin-2-yl]methyl]-2- methylpiperidine-4-carboxylic acid), ENMD-2076 (6-(4-methylpiperazin-1-yl)-N-(5-methyl-1H-pyrazol- 3-yl)-2-[(E)-2-phenylethenyl]pyrimidin-4-amine), TAK-901 (5-(3-ethylsulfonylphenyl)-3,8-dimethyl-N- (1-methylpiperidin-4-yl)-9H-pyrido[
  • AKT Inhibitors Provided herein is the method according to anyone of Embodiments 213-220, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an AKT inhibitor.
  • Exemplary AKT inhibitors for use in the methods provided herein include, but are not limited to, afuresertib, capivasertib, ipatasertib, uprosertib, BAY1125976 (2-[4-(1-aminocyclobutyl)phenyl]-3- phenylimidazo[1,2-b]pyridazine-6-carboxamide), ARQ 092 (3-[3-[4-(1-aminocyclobutyl)phenyl]-5- phenylimidazo[4,5-b]pyridin-2-yl]pyridin-2-amine), MK2206 (8-[4-(1-aminocyclobutyl)phenyl]-9- phenyl
  • Arginase Inhibitors Provided herein is the method according to anyone of Embodiments 213-220, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an arginase inhibitor.
  • Exemplary arginase inhibitors for use in the methods provided herein include, but are not limited to, numidargistat and CB 280.
  • CDK4/6 Inhibitors Provided herein is the method according to anyone of Embodiments 213-220, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a CDK4/6 inhibitor.
  • CDK 4/6 refers to cyclin dependent kinases (“CDK”) 4 and 6, which are members of the mammalian serine/threonine protein kinases.
  • CDK 4/6 inhibitor refers to a compound that is capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of CDK 4 and/or 6.
  • CDK 4/6 inhibitors for use in the methods provided herein include, but are not limited to, abemaciclib, palbociclib, ribociclib, trilaciclib, and PF-06873600 ((pyrido[2,3-d]pyrimidin-7(8H)-one, 6-(difluoromethyl)-8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-[[1-(methylsulfony1)-4- piperidinyl]amino]).
  • the CDK4/6 inhibitor is palbociclib.
  • ErbB Family Inhibitors Provided herein is the method according to anyone of Embodiments 213-220, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an ErbB family inhibitor.
  • the term “ErbB family” as used herein refers to a member of a mammalian transmembrane protein tyrosine kinase family including: ErbB1 (EGFR HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4).
  • ErbB family inhibitor refers to an agent, e.g., a compound or antibody, that is capable of negatively modulating or inhibiting all or a portion of the activity of at least one member of the ErbB family.
  • the modulation or inhibition of one or more ErbB tyrosine kinase may occur through modulating or inhibiting kinase enzymatic activity of one or more ErbB family member or by blocking homodimerization or heterodimerization of ErbB family members.
  • the ErbB family inhibitor is an EGFR inhibitor, e.g., an anti-EGFR antibody.
  • Exemplary anti-EGFR antibodies for use in the methods provided herein include, but are not limited to, zalutumumab, nimotuzumab, matuzumab, necitumumab, panitumumab, and cetuximab.
  • the anti-EGFR antibody is cetuximab.
  • the anti-EGFR antibody is panitumumab.
  • the ErbB family inhibitor is a HER2 inhibitor, e.g., an anti-HER2 antibody.
  • Exemplary anti-HER-2 antibodies for use in the methods provided herein include, but are not limited to, pertuzumab, trastuzumab, and trastuzumab emtansine.
  • the ErbB family inhibitor is a HER3 inhibitor, e.g., an anti-HER3 antibody, such as HMBD-001 (Hummingbird Bioscience).
  • the ErbB family inhibitor is a combination of an anti-EGFR antibody and anti-HER2 antibody.
  • the ErbB family inhibitor is an irreversible inhibitor.
  • Exemplary irreversible ErbB family inhibitors for use in the methods provided herein include, but are not limited to, afatinib, dacomitinib, canertinib, poziotinib, AV 412 ((N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-methyl-3-(4- methyl-1-piperazinyl)-1-butyn-1-yl]-6-quinazolinyl]-2-propenamide)), PF 6274484 ((N-[4-[(3-chloro-4- fluorophenyl)amino]-7-methoxy-6-quinazolinyl]-2-propenamide), and HKI 357 ((E)-N-[4-[3-chloro-4- [(3-fluorophenyl)methoxy]anilino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(d
  • the irreversible ErbB family inhibitor is afatinib. In one embodiment, the irreversible ErbB family inhibitor is dacomitinib. In one embodiment, the ErbB family inhibitor is a reversible inhibitor.
  • Exemplary reversible ErbB family inhibitors for use in the methods provided herein include, but are not limited to erlotinib, gefitinib, sapitinib, varlitinib, tarloxotinib, TAK-285 (N-(2-(4-((3-chloro-4-(3- (trifluoromethyl)phenoxy)phenyl)amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl)-3-hydroxy-3- methylbutanamide), AEE788 ((S)-6-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-N-(1-phenylethyl)-7H- pyrrolo
  • the reversible ErbB family inhibitor is sapitinib. In one embodiment, the reversible ErbB family inhibitor is tarloxotinib.
  • ERK Inhibitors Provided herein is the method according to anyone of Embodiments 213-220, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an ERK inhibitor.
  • Exemplary ERK inhibitors for use in the methods provided herein include, but are not limited to, ulixertinib, ravoxertinib, CC-90003 (N-[2-[[2-[(2-methoxy-5-methylpyridin-4-yl)amino]-5- (trifluoromethyl)pyrimidin-4-yl]amino]-5-methylphenyl]prop-2-enamide), LY3214996 (6,6-dimethyl-2- [2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-5-(2-morpholin-4-ylethyl)thieno[2,3-c]pyrrol-4-one), KO-947 (1,5,6,8-tetrahydro-6-(phenylmethyl)-3-(4-pyridinyl)-7H-pyrazolo[4,3-g]quinazolin-7-one), ASTX029, LTT462, and JSI-1187.
  • FAK Inhibitors Provided herein is the method according to anyone of Embodiments 213-220, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a FAK inhibitor.
  • Exemplary FAK inhibitors for use in the methods provided herein include, but are not limited to, GSK2256098 (2-[[5-chloro-2-[(5-methyl-2-propan-2-ylpyrazol-3-yl)amino]pyridin-4-yl]amino]-N- methoxybenzamide), PF-00562271 (N-methyl-N-[3-[[[2-[(2-oxo-1,3-dihydroindol-5-yl)amino]-5- (trifluoromethyl)pyrimidin-4-yl]amino]methyl]pyridin-2-yl]methanesulfonamide), VS-4718 (2-[[2-(2- methoxy-4-morpholin-4-ylanil
  • FGFR Inhibitors Provided herein is the method according to anyone of Embodiments 213-220, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an FGFR inhibitor.
  • Exemplary FGFR inhibitors for use in the methods provided herein include, but are not limited to, futibatinib, pemigatinib, ASP5878 (2-[4-[[5-[(2,6-difluoro-3,5-dimethoxyphenyl)methoxy]pyrimidin- 2-yl]amino]pyrazol-1-yl]ethanol), AZD4547 (N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazol-3-yl]-4- [(3S,5R)-3,5-dimethylpiperazin-1-yl]benzamide), Debio 1347 ([5-amino-1-(2-methyl-3H-benzimidazol- 5-yl
  • Glutaminase Inhibitors Provided herein is the method according to anyone of Embodiments 213-220, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a glutaminase inhibitor.
  • Exemplary glutaminase inhibitors for use in the methods provided herein include, but are not limited to, telaglenastat, IPN60090, and OP 330.
  • IGF-1R Inhibitors Provided herein is the method according to anyone of Embodiments 213-220, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an IGF-1R inhibitor.
  • IGF-1R inhibitors for use in the methods provided herein include, but are not limited to, cixutumumab, dalotuzumab, linsitinib, ganitumab, robatumumab, BMS-754807 ((2S)-1-[4-[(5- cyclopropyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl]-N-(6-fluoropyridin-3-yl)-2- methylpyrrolidine-2-carboxamide), KW-2450 (N-[5-[[4-(2-hydroxyacetyl)piperazin-1-yl]methyl]-2-[(E)- 2-(1H-indazol-3-yl)ethenyl]phenyl]-3-methylthiophene-2-carboxamide), PL225B, AVE1642, and BIIB022.
  • KIF18A Inhibitors Provided herein is the method according to anyone of Embodiments 213-220, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a KIF18A inhibitor.
  • Exemplary KIF18A inhibitors for use in the methods provided herein include, but are not limited to, the inhibitors disclosed in US 2020/0239441, WO 2020/132649, WO 2020/132651, and WO 2020/132653, each of which is herewith incorporated by reference in its entirety.
  • MCL-1 Inhibitors Provided herein is the method according to anyone of Embodiments 213-220, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an MCL-1 inhibitor.
  • MEK inhibitors for use in the methods provided herein include, but are not limited to, murizatoclax, tapotoclax, AZD 5991 ((3aR)-5-chloro-2,11,12,24,27,29-hexahydro-2,3,24,33-tetramethyl- 22H-9,4,8-(metheniminomethyno)-14,20:26,23-dimetheno-10H,20H-pyrazolo[4,3- l][2,15,22,18,19]benzoxadithiadiazacyclohexacosine-32-carboxylic acid), MIK 665 (( ⁇ R)- ⁇ -[[(5S)-5-[3- Chloro-2-methyl-4-[2-(4-methyl-1-piperazinyl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin- 4-yl]oxy]-2-[[2-(2-(
  • the MCL-1 inhibitor is murizatoclax. In another embodiment, the MCL-1 inhibitor is tapotoclax.
  • MEK Inhibitors Provided herein is the method according to anyone of Embodiments 213-220, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is MEK inhibitor.
  • MEK inhibitors for use in the methods provided herein include, but are not limited to, trametinib, cobimetinib, selumetinib, pimasertib, refametinib, PD-325901 (N-[(2R)-2,3- dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide), AZD8330 (2-(2-fluoro-4- iodoanilino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxopyridine-3-carboxamide), GDC-0623 (5-(2-fluoro- 4-iodoanilino)-N-(2-hydroxyethoxy)imidazo[1,5-a]pyridine-6-carboxamide), RO4987655 (3,4-difluoro- 2-(2-fluoro-4-iodoanilino)-N-(2-hydroxye)
  • the MEK inhibitor is trametinib.
  • mTOR Inhibitors Provided herein is the method according to anyone of Embodiments 213-220, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an mTOR inhibitor.
  • Exemplary mTOR inhibitors for use in the methods provided herein include, but are not limited to, everolimus, rapamycin, zotarolimus (ABT-578), ridaforolimus (deforolimus, MK-8669), sapanisertib, buparlisib, pictilisib, vistusertib, dactolisib, Torin-1 (1-(4-(4-propionylpiperazin-1-yl)-3- (trifluoromethyl)cyclohexyl)-9-(quinolin-3-yl)benzo[h][1,6]naphthyridin-2(1H)-one), GDC-0349 ((S)-1- ethyl-3-(4-(4-(3-methylmorpholino)-7-(oxetan-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2- yl)phenyl)urea
  • the mTOR inhibitor is everolimus.
  • PD-1 Inhibitors Provided herein is the method according to anyone of Embodiments 213-220, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a PD-1 inhibitor.
  • Exemplary PD-1 inhibitors for use in the methods provided herein include, but are not limited to, pembrolizumab, nivolumab, cemiplimab, spartalizumab (PDR001), camrelizumab (SHR1210), sintilimab (IBI308), tislelizumab (BGB-A317), toripalimab (JS 001), dostarlimab (TSR-042, WBP-285), INCMGA00012 (MGA012), AMP-224, AMP-514, and the anti-PD-1 antibody as described in US 10,640,504 B2 (the “Anti-PD-1 Antibody A,” column 66, line 56 to column 67, line 24 and column 67, lines 54-57), which is incorporated herein by reference.
  • the PD-1 inhibitor is pembrolizumab. In another embodiment the PD-1 inhibitor is the Anti-PD-1 Antibody A.
  • PD-L1 Inhibitors Provided herein is the method according to anyone of Embodiments 213-220, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a PD-L1 inhibitor.
  • Exemplary PD-L1 inhibitors for use in the methods provided herein include, but are not limited to, atezolizumab, avelumab, durvalumab, ZKAB001, TG-1501, SHR-1316, MSB2311, MDX-1105, KN035, IMC-001, HLX20, FAZ053, CS1001, CK-301, CBT-502, BGB-A333, BCD-135, and A167.
  • the PD-L1 inhibitor is atezolizumab.
  • PI3K Inhibitors Provided herein is the method according to anyone of Embodiments 213-220, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a PI3K inhibitor.
  • PI3K inhibitors for use in the methods provided herein include, but are not limited to, idelalisib, copanlisib, duvelisib, alpelisib, taselisib, perifosine, buparlisib, umbralisib, pictilisib, dactolisib, voxtalisib, sonolisib, tenalisib, serabelisib, acalisib, CUDC-907 (N-hydroxy-2-[[2-(6- methoxypyridin-3-yl)-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-yl]methyl-methylamino]pyrimidine-5-
  • Raf Kinase Inhibitors Provided herein is the method according to anyone of Embodiments 213-220, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a Raf kinase inhibitor.
  • RAF kinase refers to a member of a mammalian serine/threonine kinases composed of three isoforms (C-Raf, B-Raf and A-Raf) and includes homodimers of each isoform as well as heterodimers between isoforms, e.g., C-Raf/B-Raf heterodimers.
  • Raf kinase inhibitor refers to a compound that is capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of one or more member of the Raf family kinases, or is capable of disrupting Raf homodimer or heterodimer formation to inhibit activity.
  • the Raf kinase inhibitor includes, but is not limited to, encorafenib, sorafenib, lifirafenib, vemurafenib, dabrafenib, PLX-8394 (N-(3-(5-(2-cyclopropylpyrimidin-5-yl)-3a,7a- dihydro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-3-fluoropyrrolidine-1-sulfonamide), Raf-709 (N-(2-methyl-5,-morpholino-6’-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3'-bipyridin]-5-yl)-3- (trifluoromethyl)benzamide), LXH254 (N-(3-(2-(2-hydroxyethoxy)-6- morpholinopyridin-4-yl)-4-
  • the Raf kinase inhibitor is encorafenib. In one embodiment, the Raf kinase inhibitor is sorafenib. In one embodiment, the Raf kinase inhibitor is lifirafenib.
  • SHP2 Inhibitors Provided herein is the method according to anyone of Embodiments 213-220, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a SHP2 inhibitor.
  • Exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, SHP-099 (6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine dihydrochloride), RMC-4550 ([3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-(2,3-dichlorophenyl)-5- methylpyrazin-2-yl]methanol), TNO155, (3S,4S)-8-[6-amino-5-(2-amino-3-chloropyridin-4- yl)sulfanylpyrazin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine), and RMC-4630 (Revolution Medicine).
  • the SHP inhibitor for use in the methods provided herein is RMC-4630 (Revolution Medicine).
  • exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, 3-[(1R,3R)-1-amino-3-methoxy-8-azaspiro[4.5]dec-8-yl]-6-(2,3- dichlorophenyl)-5-methyl-2-pyrazinemethanol (CAS 2172651-08-8), 3-[(3S,4S)-4-amino-3-methyl-2- oxa-8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-methyl-2-pyrazinemethanol (CAS 2172652- 13-8), 3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-6-[[3-chloro-2-(3-hydroxy-1- azet
  • exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to, 1-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-4-methyl- 4-piperidinamine (CAS 2240981-75-1), (1R)-8-[5-(2,3-dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin- 8-yl]-8-azaspiro[4.5]decan-1-amine (CAS 2240981-78-4), (3S,4S)-8-[7-(2,3-dichlorophenyl)-6- methylpyrazolo[1,5-a]pyrazin-4-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (CAS 2240982-45-8), (3S,4S)-8-[7-[(2-amino-3-chloro-4-pyridinyl)thio]
  • the SHP inhibitor for use in the methods provided herein is (1R)-8-[5-(2,3- dichlorophenyl)-6-methylimidazo[1,5-a]pyrazin-8-yl]-8-azaspiro[4.5]decan-1-amine (CAS 2240981-78- 4).
  • exemplary SHP2 inhibitors for use in the methods provided herein include, but are not limited to 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5- hydroxy-2-pyridinemethanol (CAS 2238840-54-3), 3-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-6-[(2,3- dichlorophenyl)thio]-5-hydroxy-2-pyridinemethanol (CAS 2238840-56-5), 5-[(1R)-1-amino-8- azaspiro[4.5]dec-8-yl]-2-(2,3-dichlorophenyl)-3-pyridinol (CAS 2238840-58-7), 3-[(1R)-1-amino-8- azaspiro[4.5]dec-8-yl]-6-(2,3-dichlorophenyl)-5-methyl-2-pyridine
  • the SHP inhibitor for use in the methods provided herein is 3-[(1R)-1-amino- 8-azaspiro[4.5]dec-8-yl]-6-[(2,3-dichlorophenyl)thio]-5-hydroxy-2-pyridinemethanol (CAS 2238840-56- 5).
  • the SHP2 inhibitor for use in the methods provided herein is an inhibitor disclosed in US 10,590,090 B2, US 2020/017517 A1, US 2020/017511 A1, or WO 2019/075265 A1, each of which is herewith incorporated by reference in its entirety.
  • SOS1 Inhibitors Provided herein is the method according to anyone of Embodiments 213-220, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is an SOS1 inhibitor.
  • exemplary SOS1 inhibitors for use in the methods provided herein include, but are not limited to, BI 3406 (N-[(1R)-1-[3-amino-5-(trifluoromethyl)phenyl]ethyl]-7-methoxy-2-methyl-6-[(3S)-oxolan-3- yl]oxyquinazolin-4-amine), and BI 1701963.
  • Src Kinase Inhibitors Provided herein is the method according to anyone of Embodiments 213-220, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is a Src kinase inhibitor.
  • the term “Src kinase” as used herein refers to a member of a mammalian nonreceptor tyrosine kinase family including: Src, Yes, Fyn, and Fgr (SrcA subfamily); Lck, Hck, Blk, and Lyn (SrcB subfamily), and Frk subfamily.
  • Src kinase inhibitor refers to a compound that is capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of one or more member of the Src kinases.
  • Exemplary Src kinase inhibitors for use in the methods provided herein include, but are not limited to, dasatinib, ponatinib, vandetanib, bosutinib, saracatinib, KX2-391 (N-benzyl-2-(5-(4-(2- morpholinoethoxy)phenyl)pyridin-2-yl)acetamide), SU6656 ((Z)-N,N-dimethyl-2-oxo-3-((4,5,6,7- tetrahydro-1H-indol-2-yl)methylene)indoline-5-sulfonamide), PP 1 (1-(tert-butyl)-3-(p-tolyl)-1H
  • the Src kinase inhibitor is dasatinib. In one embodiment, the Src kinase inhibitor is saracatinib. In one embodiment, the Src kinase inhibitor is ponatinib. In one embodiment, the Src kinase inhibitor is vandetanib. In one embodiment, the Src kinase inhibitor is KX-01.
  • Chemotherapeutic Agents Provided herein is the method according to anyone of Embodiments 213-220, which further comprises simultaneous, separate, or sequential administration of an effective amount of a second compound, wherein the second compound is one or more chemotherapeutic agent.
  • chemotherapeutic agents for use in the methods provided herein include, but are not limited to, leucovorin calcium (calcium folinate), 5-fluorouracil, irinotecan, oxaliplatin, cisplatin, carboplatin, pemetrexed, docetaxel, paclitaxel, gemcitabine, vinorelbine, chlorambucil, cyclophosphamide, and methotrexate.
  • Stereoisomers may contain, for example, double bonds, one or more asymmetric carbon atoms, and bonds with a hindered rotation, and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers (E/Z)), enantiomers, diastereomers, and atropoisomers.
  • double-bond isomers i.e., geometric isomers (E/Z)
  • enantiomers e.e., diastereomers, and atropoisomers.
  • the scope of the instant disclosure is to be understood to encompass all possible stereoisomers of the illustrated compounds, including the stereoisomerically pure form (for example, geometrically pure, enantiomerically pure, diastereomerically pure, and atropoisomerically pure) and stereoisomeric mixtures (for example, mixtures of geometric isomers, enantiomers, diastereomers, and atropoisomers, or mixture of any of the foregoing) of any chemical structures disclosed herein (in whole or in part), unless the stereochemistry is specifically identified.
  • stereoisomerically pure form for example, geometrically pure, enantiomerically pure, diastereomerically pure, and atropoisomerically pure
  • stereoisomeric mixtures for example, mixtures of geometric isomers, enantiomers, diastereomers, and atropoisomers, or mixture of any of the foregoing
  • stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. If the stereochemistry of a structure or a portion of a structure is indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing only the stereoisomer indicated, unless otherwise noted.
  • (4R)-4-methoxy-5-methyl-4,5,6,7-tetrahydro-2H-isoindole represents (4R,5R)-4- methoxy-5-methyl-4,5,6,7-tetrahydro-2H-isoindole and (4R,5S)-4-methoxy-5-methyl-4,5,6,7-tetrahydro- 2H-isoindole.
  • the chemical name 7-chloro-6-fluoro-1-(2-isopropyl-4-methylpyridin-3- yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione represents (M)-7-chloro-6-fluoro-1-(2-isopropyl-4- methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione and (P)-7-chloro-6-fluoro-1-(2-isopropyl- 4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.
  • stereoisomer or “stereoisomerically pure” compound as used herein refers to one stereoisomer (for example, geometric isomer, enantiomer, diastereomer and atropoisomer) of a compound that is substantially free of other stereoisomers of that compound.
  • a stereoisomerically pure compound having one chiral center will be substantially free of the mirror image enantiomer of the compound and a stereoisomerically pure compound having two chiral centers will be substantially free of other enantiomers or diastereomers of the compound.
  • a typical stereoisomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and equal or less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and equal or less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and equal or less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and equal or less than about 3% by weight of the other stereoisomers of the compound.
  • This disclosure also encompasses the pharmaceutical compositions comprising stereoisomerically pure forms and the use of stereoisomerically pure forms of any compounds disclosed herein.
  • this disclosure also encompasses pharmaceutical compositions comprising mixtures of stereoisomers of any compounds disclosed herein and the use of said pharmaceutical compositions or mixtures of stereoisomers. These stereoisomers or mixtures thereof may be synthesized in accordance with methods well known in the art and methods disclosed herein. Mixtures of stereoisomers may be resolved using standard techniques, such as chiral columns or chiral resolving agents. Further, this disclosure encompasses pharmaceutical compositions comprising mixtures of any of the compounds disclosed herein and one or more other active agents disclosed herein.
  • isotopes suitable for inclusion in the compounds disclosed herein include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • isotopically-labelled compounds of Formula I for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • radioactive isotopes tritium ( 3 H) and carbon-14 ( 14 C) are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • substitution with isotopes such as deuterium ( 2 H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be advantageous in some circumstances.
  • substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N can be useful in Positron Emission Topography (PET) studies, for example, for examining target occupancy.
  • PET Positron Emission Topography
  • Isotopically-labelled compounds of the compounds disclosed herein can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying General Synthetic Schemes and Examples using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously employed.
  • Solvates As discussed above, the compounds disclosed herein and the stereoisomers, tautomers, and isotopically-labeled forms thereof or a pharmaceutically acceptable salt of any of the foregoing may exist in solvated or unsolvated forms.
  • solvate refers to a molecular complex comprising a compound, or a pharmaceutically acceptable salt thereof as described herein and a stoichiometric or non-stoichiometric amount of one or more pharmaceutically acceptable solvent molecules. If the solvent is water, the solvate is referred to as a “hydrate.” Accordingly, the scope of the instant disclosure is to be understood to encompass all solvents of the compounds disclosed herein and the stereoisomers, tautomers and isotopically-labeled forms thereof or a pharmaceutically acceptable salt of any of the foregoing. Miscellaneous Definitions This section will define additional terms used to describe the scope of the compounds, compositions and uses disclosed herein.
  • aryl refers to an aromatic hydrocarbon group having 6-20 carbon atoms in the ring portion. Typically, aryl is monocyclic, bicyclic or tricyclic aryl having 6-20 carbon atoms. Furthermore, the term “aryl” as used herein, refers to an aromatic substituent which can be a single aromatic ring, or multiple aromatic rings that are fused together.
  • Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl, each of which may optionally be substituted with 1-4 substituents, such as alkyl, trifluoromethyl, cycloalkyl, halogen, hydroxy, alkoxy, acyl, alkyl-C(O)-O-, aryl-O-, heteroaryl-O-, amino, thiol, alkyl-S-, aryl-S--- nitro, cyano, carboxy, alkyl-O-C(O)--, carbamoyl, alkyl-S(O)-, sulfonyl, sulfonamido, phenyl, and heterocyclyl.
  • substituents such as alkyl, trifluoromethyl, cycloalkyl, halogen, hydroxy, alkoxy, acyl, alkyl-C(O)-O-, aryl-O-, heteroary
  • C 1-4 alkyl refers to a straight or branched chain hydrocarbon containing from 1 to 4, and 1 to 6 carbon atoms, respectively.
  • Representative examples of C 1-4 alkyl or C 1-6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec- butyl, iso-butyl, tert-butyl, pentyl and hexyl.
  • C 1-4 alkylene and “C 1-6 alkylene” refer to a straight or branched divalent alkyl group as defined herein containing 1 to 4, and 1 to 6 carbon atoms, respectively.
  • alkylene examples include, but are not limited to, methylene, ethylene, n-propylene, iso-propylene, n-butylene, sec- butylene, iso-butylene, tert-butylene, n-pentylene, isopentylene, neopentylene, n-hexylene and the like.
  • C 2-4 alkenyl refers to a saturated hydrocarbon containing 2 to 4 carbon atoms having at least one carbon-carbon double bond. Alkenyl groups include both straight and branched moieties.
  • C 2-4 alkenyl include, but are not limited to, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, and butenyl.
  • C 2-4 alkynyl refers to a saturated hydrocarbon containing 2 to 4 carbon atoms having at least one carbon-carbon triple bond. The term includes both straight and branched moieties.
  • Representative examples of C 3-6 alkynyl include, but are not limited to, ethynyl, 1 -propynyl, 2- propynyl, 2-butynyl and 3-butynyl.
  • C 1-4 alkoxy or “C 1-6 alkoxy” as used herein refers to –OR # , wherein R # represents a C 1- 4alkyl group or C1-6alkyl group, respectively, as defined herein.
  • Representative examples of C 1-4 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, iso-propoxy, and butoxy.
  • Representative examples of C 1-6 alkoxy include, but are not limited to, ethoxy, propoxy, iso-propoxy, and butoxy.
  • C 3-8 cycloalkyl refers to a saturated carbocyclic molecule wherein the cyclic framework has 3 to 8 carbons.
  • C 3-8 cycloalkyl include, but are not limited to, cyclopropyl and cyclobutyl.
  • deutero as used herein as a prefix to another term for a chemical group refers to a modification of the chemical group, wherein one or more hydrogen atoms are substituted with deuterium (“D” or “ 2 H”).
  • D deuterium
  • C 1-4 deuteroalkyl refers to a C 1-4 alkyl as defined herein, wherein one or more hydrogen atoms are substituted with D.
  • C 1-4 deuteroalkyl include, but are not limited to, -CH 2 D, -CHD 2 , -CD 3 , -CH 2 CD 3 , -CDHCD 3 , -CD 2 CD 3 , -CH(CD 3 ) 2 , - CD(CHD 2 ) 2 , and -CH(CH 2 D)(CD 3 ).
  • halogen refers to –F, -CI, -Br, or -I.
  • halo as used herein as a prefix to another term for a chemical group refers to a modification of the chemical group, wherein one or more hydrogen atoms are substituted with a halogen as defined herein.
  • C 1- 4 haloalkyl refers to a C 1-4 alkyl as defined herein, wherein one or more hydrogen atoms are substituted with a halogen.
  • Representative examples of C 1-4 haloalkyl include, but are not limited to, -CH 2 F, -CHF 2 , - CF 3 , -CHFCl, -CH 2 CF 3 , -CFHCF 3 , -CF 2 CF 3 , -CH(CF 3 ) 2 , -CF(CHF 2 ) 2 , and -CH(CH 2 F)(CF 3 ).
  • heteroaryl refers to a 5-20 membered monocyclic- or bicyclic- or tricyclic-aromatic ring system, having 1 to 8 heteroatoms selected from N, O and S.
  • the heteroaryl is a 5-10 membered ring system (e.g., 5-7 membered monocycle, an 8-10 membered bicycle or a 11-14 membered tricycle) or a 5-7 membered ring system.
  • Exemplary monocyclic heteroaryl groups include 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3-, or 4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-, or 5- pyrazinyl, 2-pyrazinyl, and 2-, 4-, and 5-pyrimidinyl.
  • Exemplary bicyclic heteroaryl groups include 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8- isoquinolinyl, 1-, 2-, 4-, 5-, 6-, 7-, or 8-benzimidazolyl and 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-indolyl.
  • heteroaryl also refers to a group in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings.
  • heterocycle refers to a saturated or unsaturated non-aromatic ring or ring system, e.g., which is a 4-, 5-, 6-, or 7-membered monocyclic, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic or 10-, 11-, 12-, 13-, 14- or 15-membered tricyclic ring system and contains at least one heteroatom selected from O, S and N, where the N and S can also optionally be oxidized to various oxidation states.
  • the heterocyclic group can be attached to a heteroatom or a carbon atom.
  • the heterocyclyl can include fused or bridged rings as well as spirocyclic rings.
  • heterocycles include tetrahydrofuran, dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine, azetidine, thiazolidine, morpholine, and the like.
  • pharmaceutically acceptable refers to generally recognized for use in subjects, particularly in humans.
  • pharmaceutically acceptable salt refers to a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, for example, an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-
  • excipient refers to a broad range of ingredients that may be combined with a compound or salt disclosed herein to prepare a pharmaceutical composition or formulation.
  • excipients include, but are not limited to, diluents, colorants, vehicles, anti-adherants, glidants, disintegrants, flavoring agents, coatings, binders, sweeteners, lubricants, sorbents, preservatives, and the like.
  • subject refers to humans and mammals, including, but not limited to, primates, cows, sheep, goats, horses, dogs, cats, rabbits, rats, and mice. In one embodiment the subject is a human.
  • therapeutically effective amount refers to that amount of a compound disclosed herein that will elicit the biological or medical response of a tissue, a system, or subject that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • GENERAL SYNTHETIC PROCEDURES The compounds provided herein can be synthesized according to the procedures described in this and the following sections.
  • the compounds disclosed herein may also be synthesized by alternate routes utilizing alternative synthetic strategies, as appreciated by persons of ordinary skill in the art. It should be appreciated that the general synthetic procedures and specific examples provided herein are illustrative only and should not be construed as limiting the scope of the present disclosure in any manner.
  • the compounds of Formula I can be synthesized according to the following schemes. Any variables used in the following schemes are the variables as defined for Formula I, unless otherwise noted. All starting materials are either commercially available, for example, from Merck Sigma-Aldrich Inc., Fluorochem Ltd, and Enamine Ltd. or known in the art and may be synthesized by employing known procedures using ordinary skill. Starting material may also be synthesized via the procedures disclosed herein. Suitable reaction conditions, such as, solvent, reaction temperature, and reagents, for the Schemes discussed in this section, may be found in the examples provided herein.
  • step A compound (1) is treated with sodium thiomethoxide in a solvent such as tetrahydrofuran to give compound (2).
  • step B compound (2) is either pre-treated with a fluoride source such as potassium fluoride, or directly undergoes S N Ar reaction with a nucleophile having the formula R 1 -L-H in a solvent such as dimethylsulfoxide, or mixture of solvents such as tetrahydrofuran and N,N-dimethylforamide, in the presence of a base such as sodium hydride or cesium carbonate, with or without a nucleophilic catalyst such as 1,4-diazabicyclo[2.2.2]octane, to give compound (3).
  • a fluoride source such as potassium fluoride
  • step B compound (2) is either pre-treated with a fluoride source such as potassium fluoride, or directly undergoes S N Ar reaction with a nucleophile having the formula R 1 -L-H in a solvent such as dimethylsulfox
  • step C compound (3) is coupled with an organometallic reagent derived from benzothiophene such as a boronic acid (ester) to provide compound (4).
  • This coupling reaction proceeds in a solvent such as 1,4-dioxane and a catalyst such as Pd 2 (dba) 3 and (R)-MOP, with or without a base such as potassium phosphate.
  • step D compound (4) is treated with sulfuryl chloride in a solvent such as dichloromethane to give compound (5).
  • step E compound (5) undergoes S N Ar reaction with optionally substituted amine in a solvent such as acetonitrile and in the presence of a base such as N,N-diisopropylethylamine to give compound (6).
  • the species R 8 will contain protecting group(s), which can be removed after step E in the synthetic sequence.
  • Compounds of Formula (I) can be prepared according to Scheme II.
  • step A compound (1) undergoes S N Ar reaction with optionally substituted amine in a solvent such as acetonitrile and in the presence of a base such as N,N-diisopropylethylamine to give compound (6).
  • step B compound (6) is either pre-treated with a fluoride source such as potassium fluoride, or directly undergoes S N Ar reaction with a nucleophile having the formula R 1 -L-H in a solvent such as dimethylsulfoxide, or mixture of solvents such as tetrahydrofuran and N,N-dimethylforamide, in the presence of a base such as sodium hydride or cesium carbonate, with or without a nucleophilic catalyst such as 1,4-diazabicyclo[2.2.2]octane, to give compound (7).
  • step C compound (7) is coupled with an organometallic reagent derived from benzothiophene such as a boronic acid (ester) to provide compound (I).
  • a fluoride source such as potassium fluoride
  • S N Ar reaction with a nucleophile having the formula R 1 -L-H in a solvent such as dimethylsulfoxide, or mixture of solvents such as tetrahydrofur
  • Preparative HPLC Method where so indicated, the compounds described herein were purified via reverse phase HPLC using Waters FractionLynx semi-preparative HPLC-MS system utilizing one of the following two HPLC columns: (a) Phenomenex Gemini column (5 micron, C18, 150x30 mm) or (b) Waters X-select CSH column (5 micron, C18, 100x30 mm). A typical run through the instrument included: eluting at 45 mL/min with a linear gradient of 10% (v/v) to 100% MeCN (0.1% v/v formic acid) in water (0.1% formic acid) over 10 minutes; conditions can be varied to achieve optimal separations.
  • Step 1 4-(4-Methoxybenzyl)-1,4-oxazepan-6-one.
  • 1,4-oxazepan-6- one hydrochloride (0.30 g, 1.98 mmol, AA BLOCKS LLC)
  • 4-methoxybenzyl chloride (0.37 g, 0.32 mL, 2.38 mmol, TCI America)
  • DIPEA 0.77 g, 1.0 mL, 5.94 mmol, Sigma-Aldrich Corporation
  • DCM 10 mL
  • Step 3 Chiral separation.4-(4-Methoxybenzyl)-6-methyl-1,4-oxazepan-6-ol (0.65 g, 2.59 mmol) was purified via SFC using a Chiralpak AD, 30 ⁇ 150 mm, 5 ⁇ m, column with a mobile phase of 20% methanol with 0.2% triethylamine using a flowrate of 200 mL/min to generate 246 mg of peak 1 with an ee of >99% and 292 mg of peak 2 with an ee of >99%.
  • Step 4 6-Methyl-1,4-oxazepan-6-ol hydrochloride.
  • Step 1 Benzyl 3-hydroxy-3-methylazepane-1-carboxylate.
  • 3-methylazepan-3-ol hydrochloride (0.25 g, 1.51 mmol, Asta-tech)
  • benzyl chloroformate (0.28 g, 0.24 mL, 1.66 mmol, Oakwood Products, Inc.)
  • DIPEA 0.59 g, 0.8 mL, 4.53 mmol, Sigma- Aldrich Corporation
  • THF 5.0 mL
  • Benzyl 3-hydroxy-3-methylazepane-1-carboxylate (0.24 g) was purified via SFC using a Chiralpak IG, 21 ⁇ 250 mm, 5 ⁇ m, column with a mobile phase of 20% methanol with 0.2% triethylamine using a flowrate of 80 mL/min to generate 89 mg of peak 1 with an ee of >99% and 91 mg of peak 2 with an ee of >99%.
  • Step 3 3-Methylazepan-3-ol hydrochloride. Benzyl 3-hydroxy-3-methylazepane-1-carboxylate (89 mg, 0.34 mmol, Peak 1) was dissolved in ethanol (1.7 mL).
  • Step 2 7-Bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(methylthio)quinazoline.
  • Step 3 tert-Butyl (4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4-(methylthio)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2- yl)carbamate.
  • Step 2 tert-Butyl (4-(4-(azepan-1-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate.
  • Step 3 2-Amino-4-(4-(azepan-1-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile.
  • Step 2 4-(7-Bromo-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)quinazolin-4-yl)-1,4-oxazepane.
  • Step 3 tert-Butyl (4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2- yl)carbamate.
  • the reaction mixture was stirred at 80 °C for 1 h.
  • the crude mixture was purified by column chromatography on silica gel, eluting with a gradient of 0 - 50% 3:1 EtOAc/EtOH in heptane with 2% triethylamine additive to yield tert-butyl (4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)quinazolin-7-yl)-3-cyano-7- fluorobenzo[b]thiophen-2-yl)carbamate (0.21 g, 0.29 mmol, 56 % yield).
  • Step 4 2-Amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4-(1,4-oxazepan-4-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3- carbonitrile.
  • Step 2 2-Amino-4-(6-ethyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)-7-fluorobenzo[b]thiophene- 3-carbonitrile.
  • reaction mixture was purified by reverse phase HPLC to afford tert-butyl (3-cyano-7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-6-hydroxy-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7-yl)benzo[b]thiophen-2- yl)carbamate (30 mg, 0.04 mmol, 50 % yield) as orange solid.
  • Step 2 2-Amino-7-fluoro-4-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-6-hydroxy-4-(6-hydroxy-6-methyl-1,4-oxazepan-4-yl)quinazolin-7- yl)benzo[b]thiophene-3-carbonitrile.
  • Step 2 2-Amino-4-(6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-4-(2-hydroxy-6-azaspiro[3.5]nonan-6-yl)quinazolin-7-yl)-7- fluorobenzo[b]thiophene-3-carbonitrile.
  • Step 1 tert-Butyl (4-(6-chloro-4-(5,6-dihydro-2H-pyran-3-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-3-cyano-7- fluorobenzo[b]thiophen-2-yl)carbamate.
  • Step 2 2-Amino-4-(6-chloro-4-(5,6-dihydro-2H-pyran-3-yl)-8-fluoro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3- carbonitrile bis(2,2,2-trifluoroacetate).
  • Step 1 tert-Butyl (4-(6-chloro-4-cyclopropyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate.
  • Step 2 2-Amino-4-(6-chloro-4-cyclopropyl-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile bis(2,2,2- trifluoroacetate).
  • KRAS G12D TR-FRET Assay Compounds of interest were prepared in a dose-response titration in DMSO, and 80 nL were added via Labcyte Echo to each well of a 384-well plate (Perkin Elmer 6008280).
  • the His-tagged KRAS G12D protein (Amgen) was diluted to 20 nM in Assay Buffer (20 mM HEPES, pH 7.4, 10 mM MgCl 2 , 50 mM NaCl, 0.1% BSA, 0.01% Tween-20, 10 ⁇ M GDP) and 2 uL was added to the appropriate wells of the 384-well plate.
  • Biotinylated KRPep-2d substrate (Amgen) was diluted to 20 nM in Assay Buffer and 2 ⁇ L was added to all wells and incubated for 1 hour at room temperature.
  • Detection Reagent (0.4 nM LANCE Eu-W1024 Anti-6xHis (Perkin Elmer AD0401), 5 nM streptavidin-d2 (Cisbio 610SADLA) was prepared in Assay Buffer, then 4 ⁇ L was added to the plate and incubated for 1 h at rt.
  • KRAS G12D Coupled Nucleotide Exchange Assay Purified GDP-bound KRAS protein (aa 1-169), containing both G12D and C118A amino acid substitutions and an N-terminal His-tag, was pre-incubated in assay buffer (25 mM HEPES pH 7.4, 10 mM MgCl 2 , and 0.01% Triton X-100) with a compound dose-response titration for 2 h.
  • purified SOS protein (aa 564-1049) and GTP (Roche 10106399001) were added to the assay wells and incubated for an additional 30 min.
  • purified GST-tagged cRAF (aa 1-149), nickel chelate AlphaLISA acceptor beads (PerkinElmer AL108R), and AlphaScreen glutathione donor beads (PerkinElmer 6765302) were added to the assay wells and incubated for 10 min.
  • the assay plates were then read on a PerkinElmer EnVision Multilabel Reader, using AlphaScreen® technology, and data were analyzed using a 4-parameter logistic model to calculate IC 50 values.
  • AsPC-1 AsPC-1 (ATCC® CRL-1682TM) cells were cultured in RPMI 1640 Medium (ThermoFisher Scientific 11875093) containing 10% fetal bovine serum (ThermoFisher Scientific 16000044) and 1x penicillin-streptomycin-glutamine (ThermoFisher Scientific 10378016). Sixteen hours prior to compound treatment, AsPC-1 cells were seeded in 96-well cell culture plates at a density of 25,000 cells/well and incubated at 37 °C, 5% CO 2 .
  • a compound dose-response titration was diluted in growth media, added to appropriate wells of a cell culture plate, and then incubated at 37 °C, 5% CO 2 for 2 hours. Following compound treatment, cells were washed with ice-cold Dulbecco's phosphate-buffered saline, no Ca 2+ or Mg 2+ (ThermoFisher Scientific 14190144), and then lysed in RIPA buffer (50 mM Tris-HCl pH 7.5, 1% Igepal, 0.5% sodium deoxycholate, 150 mM NaCl, and 0.5% sodium dodecyl sulfate) containing protease inhibitors (Roche 4693132001) and phosphatase inhibitors (Roche 4906837001).
  • RIPA buffer 50 mM Tris-HCl pH 7.5, 1% Igepal, 0.5% sodium deoxycholate, 150 mM NaCl, and 0.5% sodium dodecyl sulfate

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Abstract

La présente invention concerne des composés utiles pour l'inhibition de KRAS G12D, G12V, G12A, G12S ou G12C. Les composés ont une formule générale I : (I) dans laquelle les variables de formule I sont définies dans la description. La présente invention concerne également des compositions pharmaceutiques comprenant les composés, des utilisations des composés, et des compositions pour le traitement, par exemple, du cancer.
PCT/US2023/062687 2022-02-16 2023-02-15 Composés de quinazoline et leur utilisation en tant qu'inhibiteurs de protéines kras mutantes Ceased WO2023159086A1 (fr)

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JP2024547690A JP2025508702A (ja) 2022-02-16 2023-02-15 キナゾリン化合物、及び変異ｋｒａｓタンパク質の阻害剤としてのその使用
AU2023222076A AU2023222076A1 (en) 2022-02-16 2023-02-15 Quinazoline compounds and use thereof as inhibtors of mutant kras proteins
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CN202380032897.3A CN118974055A (zh) 2022-02-16 2023-02-15 作为突变kras蛋白抑制剂的喹唑啉化合物及其用途
US18/838,954 US20250163064A1 (en) 2022-02-16 2023-02-15 Quinazoline compounds and uses thereof as inhibitors of mutant kras proteins
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WO2024112654A1 (fr) 2022-11-21 2024-05-30 Treeline Biosciences, Inc. Inhibiteurs de kras spirocycliques de dihydropyranopyrimidine
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
WO2025038936A1 (fr) 2023-08-17 2025-02-20 Treeline Biosciences, Inc. Inhibiteurs de dihydropyranopyrimidine kras spirocycliques
WO2025064848A1 (fr) 2023-09-21 2025-03-27 Treeline Biosciences, Inc. Inhibiteurs de kras de type dihydropyranopyrimidines spirocycliques
WO2025076288A1 (fr) 2023-10-06 2025-04-10 Amgen Inc. Polythérapie pour le traitement du cancer
WO2025080593A1 (fr) 2023-10-09 2025-04-17 Incyte Corporation Polythérapie utilisant un inhibiteur de kras g12d et un inhibiteur de pd-1 ou un inhibiteur de pd-l1
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025080592A1 (fr) 2023-10-09 2025-04-17 Incyte Corporation Polythérapie à base d'un inhibiteur de kras g12d et d'un inhibiteur d'egfr pour une utilisation dans le traitement du cancer
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
US12448400B2 (en) 2023-09-08 2025-10-21 Gilead Sciences, Inc. KRAS G12D modulating compounds
US12448399B2 (en) 2023-01-26 2025-10-21 Arvinas Operations, Inc. Cereblon-based KRAS degrading PROTACs and uses related thereto
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025245127A1 (fr) 2024-05-21 2025-11-27 Treeline Biosciences, Inc. Inhibiteurs de dihydropyranopyrimidine kras spirocycliques
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024112654A1 (fr) 2022-11-21 2024-05-30 Treeline Biosciences, Inc. Inhibiteurs de kras spirocycliques de dihydropyranopyrimidine
US12448399B2 (en) 2023-01-26 2025-10-21 Arvinas Operations, Inc. Cereblon-based KRAS degrading PROTACs and uses related thereto
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
WO2025038936A1 (fr) 2023-08-17 2025-02-20 Treeline Biosciences, Inc. Inhibiteurs de dihydropyranopyrimidine kras spirocycliques
US12448400B2 (en) 2023-09-08 2025-10-21 Gilead Sciences, Inc. KRAS G12D modulating compounds
WO2025064848A1 (fr) 2023-09-21 2025-03-27 Treeline Biosciences, Inc. Inhibiteurs de kras de type dihydropyranopyrimidines spirocycliques
WO2025076288A1 (fr) 2023-10-06 2025-04-10 Amgen Inc. Polythérapie pour le traitement du cancer
WO2025080593A1 (fr) 2023-10-09 2025-04-17 Incyte Corporation Polythérapie utilisant un inhibiteur de kras g12d et un inhibiteur de pd-1 ou un inhibiteur de pd-l1
WO2025080592A1 (fr) 2023-10-09 2025-04-17 Incyte Corporation Polythérapie à base d'un inhibiteur de kras g12d et d'un inhibiteur d'egfr pour une utilisation dans le traitement du cancer
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025245127A1 (fr) 2024-05-21 2025-11-27 Treeline Biosciences, Inc. Inhibiteurs de dihydropyranopyrimidine kras spirocycliques
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras

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